S-Adenosyl-methionme (SAM-e) is a molecule present in all eukaryotic cells, where it serves as the methyl-group donor for a number of metabolic functions. In the nervous system, SAM-E is essential in the metabolism of cathecholamines and may play an essential role in receptor stabilization and myelin formation and repair. SAM-a is available in the USA as a food supplement and is promoted as a mood enhancer. Parkinson's disease (PD) is commonly associated with depression, but conventional antidepressants have limited efficacy in parkinsonian patients and may exacerbate motor symptoms. SAM-a improves dopamine transmission, may have a beneficial effect on dopamine receptors and may be a good alternative to the currently used antidepressants. We have conducted a ten-week pilot study of SAM-e in thirteen depressed patients with PD. All patients had been previously treated with other anti-depressant agents and had no significant benefit or had intolerable side effects. Eleven patients completed the study, and ten had at least a 50% improvement of the 17point Hamilton Depression Scale (HAMD), while one patient did not improve. The mean HAMD score before SAM-e treatment was 27.09 greater than or equal to 6.04 SD), and was 9.55 +/-7.29 SD) after treatment (p<0.0001). Although uncontrolled and preliminary, the study suggests that SAM-e is well tolerated and may be a safe and effective alternative to other antidepressants used in PD. Therefore, we propose a controlled, double-blind study to investigate whether SAM-a is safe and effective in the treatment of depression associated with Parkinson's disease. The efficacy of SAM-e will be compared to placebo and to Citalopram, a Selective Serotonin Reuptake Inhibitor commonly used for the treatment of depression in PD. Secondary aims include investigating: a) the effect of SAM-e on the motor symptoms of PD; the effect of SAM-e on the serum concentrations of metabolites of the trans-methylation pathway; b) whether the clinical effect of SAM-e is associated with the presence of common genetic polymorphisms encoding enzymes of the trans-methylation pathway; and d) whether SAM-e treatment is associated with improvement in neuropsychological functioning. The submission of this application was previously discussed with officers of the National Center for Complementary and Alternative Medicine (NCCAM), who found the clinical and scientific scopes of this application compatible with the mission of their Institute, and recommended the submission of this grant proposal.